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Background: Little is known about the trends in morbidity and mortality at the population level that followed the introduction of newer once-daily long-acting bronchodilators for COPD. The purpose of the study was to evaluate whether the availability of new bronchodilators was associated with changes in the temporal trends in severe COPD exacerbations and mortality between 2007 and 2018 in the older population with COPD; and whether this association was homogeneous across sex and socioeconomic status classes. Methods: We used an interrupted time-series and three segments multivariate autoregressive models to evaluate the adjusted changes in slopes (i.e., trend effect) in monthly severe exacerbation and mortality rates after 03/2013 and 02/2015 compared to the tiotropium period (04/2007 to 02/2013). Cohorts of individuals > 65 years with COPD were created from the nationally representative database of the Quebec Integrated Chronic Disease Surveillance System in the province of Quebec, Canada. Whether these trends were similar for men and women and across different socioeconomic status classes was also assessed. Results: There were 130,750 hospitalizations for severe exacerbation and 104,460 deaths, including 24,457 (23.4%) respiratory-related deaths, over the study period (928,934 person-years). Significant changes in trends were seen after 03/2013 for all-cause mortality (-1.14%/month;95%CI -1.90% to -0.38%), which further decreased after 02/2015 (-1.78%/month;95%CI -2.70% to -0.38%). Decreases in respiratory-related mortality (-2.45%/month;95%CI -4.38% to -0.47%) and severe exacerbation (-1,90%/month;95%CI -3.04% to -0.75%) rates were only observed after 02/2015. These observations tended to be more pronounced in women than in men and in higher socioeconomic status groups (less deprived) than in lower socioeconomic status groups (more deprived). Conclusions: The arrival of newer bronchodilators was chronologically associated with reduced trends in severe exacerbation, all-cause and respiratory-related mortality rates among people with COPD > 65 years. Our findings document population benefits on key patient-relevant outcomes in the years following the introduction of newer once-daily long-acting bronchodilators and their combinations, which were likely multifactorial. Public health efforts should focus on closing the gap between lower and higher socioeconomic status groups. [ABSTRACT FROM AUTHOR]

Formulations containing more than one active ingredient are increasingly gaining popularity due to advantages with regard to patient convenience as well as reduced cost of production, packaging, and transportation. Such fixed-dose combinations (FDCs) demand for enhanced analytical methodologies and tools to efficiently achieve quality control of these complex products as compared to the conventional products containing only one active constituent. Highly efficient analytical methods can measure multiple constituents at once, improving their quality control. This review article discusses the challenges in the development of such methods due to the similarities or differences in the chemical identity of the participating drug molecules in an FDC. The latest developments in multiple analyte determination using various analytical techniques (HPLC, LC–MS, NMR, IR, powder XRD and DSC) are discussed, with a focus on special considerations in each case. The article discusses challenges with sample preparation of complex FDC products, and the use of Chemometrics and Quality by Design to develop efficient analytical methods. Lastly, an equation-based approach is proposed and demonstrated to arrive at a parameter referred to as "percentage efficiency gain" that would be useful in directly accessing the relevance and commercial benefits of a simultaneous method vis-a-vis separate methods for individual components. [Display omitted] • Complexities in analysis of fixed-dose combinations (FDCs) are discussed. • Rationalization based on chemical structures of constituent drugs is provided. • Sample preparation issues and remedies for complex FDC formulations are highlighted. • Role of Chemometrics, QbD, and DoE and other enabling tools are summarized. • Calculation of a new descriptive parameter, Percentage Efficiency Gain (%E g), is proposed. [ABSTRACT FROM AUTHOR]

The combined cilostazol and rosuvastatin therapy is frequently used for coronary artery disease treatment. This open‐label, 3 × 3 crossover clinical trial evaluated the pharmacokinetics and safety of a fixed‐dose combination (FDC) of cilostazol/rosuvastatin (200 + 20 mg) versus a concurrent administration of the separate components (SCs) under both fasted and fed conditions. Among 48 enrolled healthy adults, 38 completed the study. Participants were administered a single oral dose of cilostazol/rosuvastatin (200 + 20 mg), either as an FDC or SCs in a fasted state, or FDC in a fed state, in each period of the trial. Blood samples were taken up to 48 hours after dosing, and plasma concentrations were analyzed using validated liquid chromatography‐tandem mass spectrometry. The geometric mean ratios of FDC to SCs for area under the plasma concentration‐time curve from time zero to the last quantifiable concentration (AUClast) and maximum plasma concentration (Cmax) were 0.94/1.05 and 1.06/1.15 for cilostazol and rosuvastatin, respectively (AUClast/Cmax). Compared with that during fasting, fed‐state administration increased the AUClast and Cmax for cilostazol by approximately 72% and 160% and decreased these parameters for rosuvastatin by approximately 39% and 43%, respectively. To conclude, the FDC is bioequivalent to the SCs, with notable differences in pharmacokinetics when administered in a fed state. No significant safety differences were observed between the treatments. [ABSTRACT FROM AUTHOR]

Introduction: Dexketoprofen/tramadol 25/75 mg (DKP/TRAM) is a fixed-dose combination of a cyclooxygenase inhibitor and opioid receptor agonist. To better understand the efficacy and safety of DKP/TRAM in the treatment of moderate to severe acute lower back pain (LBP) with or without radiculopathy, we carried out a large explorative phase IV international, multicenter, prospective, randomized, double-blind, parallel group, placebo-controlled study (DANTE). Methods: A total of 538 patients with or without a history of LBP and experiencing acute LPB of moderate to severe intensity [Numerical Rating Scale-Pain Intensity (NRS-PI) score > 5] were randomized 4:4:1:1 to DKP/TRAM 25/75 mg every 8 h (n = 211), tramadol (TRAM) 100 mg (n = 207), placebo-matched DKP/TRAM (n = 59), or placebo-matched TRAM (n = 61). Results: The proportion of patients achieving the primary endpoint, defined as the time to first achieve NRS-PI score < 4 or pain intensity reduction ≥ 30% from drug intake up to 8 h after the first dose, was higher in the DKP/TRAM arm than in the placebo group, but the difference was not statistically significant (46.1% vs. 42.6%, respectively; hazard ratio 1.11; 95% confidence interval 0.775, 1.595; p = 0.566). DKP/TRAM achieved superiority over TRAM in total pain relief at 4, 6, and 8 h (p < 0.05). Conversely, in relation to the secondary endpoints, a significantly greater reduction in NRS-PI score was seen with DKP/TRAM versus placebo starting from 1 h, and this reduction remained numerically lower throughout 8 h. Summed pain intensity difference values were also significantly lower at 4, 6, and 8 h with DKP/TRAM compared to TRAM (p < 0.05). Overall, DKP/TRAM was well tolerated. Conclusion: Although the primary endpoint was not met, secondary efficacy analyses suggest the superiority of DKP/TRAM over placebo and TRAM alone in terms of total pain relief. DKP/TRAM can be considered to be an effective and safe option for the treatment of moderate to severe acute LBP. Dante Study Registration: EudraCT number: 2019–003656-37; ClinicalTrials.gov Identifier: NCT05170841. [ABSTRACT FROM AUTHOR]

Patients with diabetes face a 2‐4‐fold greater cardiovascular risk compared to those without diabetes. Both metformin and acetylsalicylic acid (aspirin) treatment have demonstrated a significant reduction in this risk. This single‐center, open‐label, sequence randomized, 2 × 2 crossover, single‐dose clinical trial evaluated the pharmacokinetics profile and comparative bioavailability of a novel oral fixed‐dose combination (FDC) of metformin/acetylsalicylic acid (500/100 mg tablet) versus the reference mono‐drugs administered concomitantly, metformin 500 mg tablet and acetylsalicylic acid 100 mg tablet, in 22 healthy Mexican adult volunteers under fasting conditions. Blood samples were collected predose and at specified intervals across a 24‐hour period following administration and were analyzed for metformin and salicylic acid using high‐performance liquid chromatography coupled with tandem mass spectrometry. Test products were considered to have comparative bioavailability if confidence intervals of natural log‐transformed (maximum plasma drug concentration (Cmax), (area under the plasma drug concentration‐time curve form 0 up to last sampling time (AUC0‐t), and (area under the plasma drug concentration‐time cruve from 0 up to infinity (AUC0∞) data were within the range of 80%‐125%. The results obtained from the present clinical study demonstrate the comparative bioavailability of the FDC when compared with the coadministration of reference mono‐drugs. There were no adverse events or adverse reactions reported throughout the study. [ABSTRACT FROM AUTHOR]

The purpose of this study was to enhance the stability of montelukast and levocetirizine for the development of a fixed-dose combination (FDC) monolayer tablet. To evaluate the compatibility of montelukast and levocetirizine, a mixture of the two drugs was prepared, and changes in the appearance characteristics and impurity content were observed in a dry oven at 60 °C. Excipients that contributed minimally to impurity increases were selected to minimize drug interactions. Mannitol, microcrystalline cellulose, croscarmellose sodium, hypromellose, and sodium citrate were chosen as excipients, and montelukast–levocetirizine FDC monolayer tablets were prepared by wet granulating the two drugs separately. A separate granulation of montelukast and levocetirizine, along with the addition of sodium citrate as a pH stabilizer, minimized the changes in tablet appearance and impurity levels. The prepared tablets demonstrated release profiles equivalent to those of commercial products in comparative dissolution tests. Subsequent stability testing at 40 ± 2 °C and 75 ± 5% RH for 6 months confirmed that the drug content, dissolution rate, and impurity content met the specified acceptance criteria. In conclusion, the montelukast–levocetirizine FDC monolayer tablet developed in this study offers a potential alternative to commercial products. [ABSTRACT FROM AUTHOR]

The incidence of allergic rhinitis (AR) in Asia and the world is steadily rising. Patients experience incomplete symptom relief despite existing treatment options, which warrants the need for new therapeutic regimes. Azelastine hydrochloride/fluticasone propionate (MP-AzeFlu), a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate has been indicated in the treatment of AR. The current review discusses the effects of MP-AzeFlu versus conventional therapies in achieving superior clinical improvement with a very rapid onset of action (5 minutes). The superiority of MP-AzeFlu in offering complete symptom control with sustained relief in patients with AR compared to the existing therapeutic options is also discussed. MP-AzeFlu has been shown to improve the quality of life for patients with AR, thereby enhancing patient adherence to therapy and establishing its preference for the treatment of AR. Currently, the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines recommend the use of a combination of intranasal corticosteroids and intranasal antihistamines as first-line treatment in patients with persistent AR with visual analog scores ≥ 5 or when prior treatment with single agents has been ineffective. Widely published data on the efficacy and safety of its prolonged use in adults and children have validated that effective treatment of AR can be achieved with MP-AzeFlu. [ABSTRACT FROM AUTHOR]

Objective: To assess the pharmacokinetics and bioequivalence of Dapagliflozin 10mg + Vildagliptin Sustained Release (SR) 100mg + Metformin SR 1000mg fixed dose combination (FDC) tablets with DAPAMAC V 10 (Dapagliflozin 10mg + Vildagliptin SR 100mg tablets) and Glycomet 1g (Metformin SR 1000 mg tablets) in healthy adult male subjects under fasting conditions. Material and Methods: This was an open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover, oral bioequivalence study. Volunteers were randomized to receive either a test product or a reference product under the fasting condition with a seven-day washout period. The pharmacokinetics parameters evaluated were maximum plasma concentration (Cmax), the area under the curve (AUC) at time t (AUC0-t), and the total area under the curve (AUC0-∞). Adverse events were also assessed as safety endpoints. Results: Twenty-four healthy adult male subjects were randomized, and 24 completed the study. The mean values for Cmax, AUC0-t, and AUC0-∞ were almost identical for test and reference products. The 90% confidence intervals of the ratios of adjusted geometric means for the pharmacokinetic parameters, i.e. Cmax, AUC0-t, and AUC0-∞ of the test product, were within the predefined bioequivalence limits of 80.00 to 125.00%. No adverse events or serious adverse events or deaths were reported during the study. All treatments were well tolerated. Conclusion: The test formulation, Dapagliflozin 10mg + Vildagliptin SR 100mg + Metformin SR 1000mg FDC, were bioequivalent to DAPAMAC V 10 (Dapagliflozin 10mg + Vildagliptin SR 100mg tablets) and Glycomet 1g (Metformin 1000mg SR tablets) in healthy adult male subjects under fasting conditions. [ABSTRACT FROM AUTHOR]

Introduction: Fixed-dose combinations (FDCs) of angiotensin II receptor blockers, calcium channel blockers, and statins are conventional therapeutic interventions prescribed for cardiovascular diseases. This study aimed at drawing a comparison between the pharmacokinetics and safety of an FDC and the corresponding individual formulations in healthy subjects. Methods: A randomized, open-label, single-dose, three-sequence, three-period, partially repeated crossover study was conducted with a cohort of healthy volunteers. A 14-day washout period was maintained between each of the three periods. In this study, candesartan cilexetil, amlodipine, and atorvastatin was administered orally as FDCs of 16/10/40 mg in study 1 and 16/5/20 mg in study 2. The maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from time zero to the time of the last quantifiable concentration (AUClast) of candesartan, amlodipine, and atorvastatin were estimated as the geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the FDC to individual formulations. If the within-subject coefficient of variation (CVwr) of Cmax was greater than 0.3, the bioequivalence (BE) range calculated using the reference-scaled average bioequivalence was used to assess whether the 90% CI was within the BE range. Results: The GMRs (90% CIs) for the AUClast for candesartan and amlodipine were 0.9612 (0.9158–1.0089)/0.9965 (0.9550–1.0397) and 1.0033 (0.9800–1.0271)/1.0067 (0.9798–1.0344), and the GMRs (90% CIs) for Cmax were 0.9600 (0.8953–1.0294)/0.9851 (0.9368–1.0359) and 1.0198 (0.9950–1.0453)/1.0003 (0.9694–1.0321) in studies 1 and 2, respectively. The extended BE ranges calculated from the CVwr of the Cmax of atorvastatin were 0.7814–1.2797 and 0.7415–1.3485, respectively. The GMRs (90% CIs) for the AUClast of atorvastatin were 1.0532 (1.0082–1.1003)/1.0252 (0.9841–1.0680), and the GMRs (90% CIs) for Cmax were 1.0630 (0.9418–1.1997)/0.9888 (0.8792–1.1120) in studies 1 and 2, respectively. Conclusion: The Cmax and AUClast values of candesartan cilexetil/amlodipine/atorvastatin 16/10/40 mg and 16/5/20 mg, respectively, were within the BE ranges. There were no clinically significant differences in safety between the two formulations. Trial Registration: ClinicalTrials.gov identifier, study 1: NCT04478097; study 2: NCT04627207. [ABSTRACT FROM AUTHOR]

Abstract Background Little is known about the trends in morbidity and mortality at the population level that followed the introduction of newer once-daily long-acting bronchodilators for COPD. The purpose of the study was to evaluate whether the availability of new bronchodilators was associated with changes in the temporal trends in severe COPD exacerbations and mortality between 2007 and 2018 in the older population with COPD; and whether this association was homogeneous across sex and socioeconomic status classes. Methods We used an interrupted time-series and three segments multivariate autoregressive models to evaluate the adjusted changes in slopes (i.e., trend effect) in monthly severe exacerbation and mortality rates after 03/2013 and 02/2015 compared to the tiotropium period (04/2007 to 02/2013). Cohorts of individuals > 65 years with COPD were created from the nationally representative database of the Quebec Integrated Chronic Disease Surveillance System in the province of Quebec, Canada. Whether these trends were similar for men and women and across different socioeconomic status classes was also assessed. Results There were 130,750 hospitalizations for severe exacerbation and 104,460 deaths, including 24,457 (23.4%) respiratory-related deaths, over the study period (928,934 person-years). Significant changes in trends were seen after 03/2013 for all-cause mortality (-1.14%/month;95%CI -1.90% to -0.38%), which further decreased after 02/2015 (-1.78%/month;95%CI -2.70% to -0.38%). Decreases in respiratory-related mortality (-2.45%/month;95%CI -4.38% to -0.47%) and severe exacerbation (-1,90%/month;95%CI -3.04% to -0.75%) rates were only observed after 02/2015. These observations tended to be more pronounced in women than in men and in higher socioeconomic status groups (less deprived) than in lower socioeconomic status groups (more deprived). Conclusions The arrival of newer bronchodilators was chronologically associated with reduced trends in severe exacerbation, all-cause and respiratory-related mortality rates among people with COPD > 65 years. Our findings document population benefits on key patient-relevant outcomes in the years following the introduction of newer once-daily long-acting bronchodilators and their combinations, which were likely multifactorial. Public health efforts should focus on closing the gap between lower and higher socioeconomic status groups.

Context: The annual incidence cases report depicts India as having the highest tuberculosis (TB) burden globally. Following a programmatic change, the daily fixed-dose combination (FDC) anti-TB treatment regimens were introduced by the Indian government’s National Tuberculosis Elimination Program (NTEP). Aims: The aim of the study was to assess the treatment outcomes among drug-sensitive pulmonary TB patients receiving daily FDC drugs and the associated factors influencing the treatment outcomes. Settings and Design: A prospective study was conducted among 300 drug-sensitive pulmonary TB cases in the Bruhat Bengaluru Mahanagara Palike (BBMP) area. Materials and Methods: The TB units and designated microscopic centers (DMCs) were selected by multistage random sampling. Data were collected through a pre-tested and semi-structured questionnaire. Patients were followed up until treatment completion. Statistical Analysis Used: Data were compiled and analyzed using IBM Statistical Package for Social Sciences (SPSS) statistics version 20.0. Descriptive statistics and the Chi-square test were used for interpretation. A P-value less than 0.05 was considered statistically significant. Results: Around 86.33% of patients were cured, 4% had completed treatment, and 1% had treatment failure. Older age, human immunodeficiency virus (HIV) reactive status, alcohol intake, tobacco use, and migrants were associated with poor outcomes. Conclusions: The daily FDC regimen had better outcomes than intermittent regimens. Smokers, alcoholics, migrants, and patients with co-morbidity need to be given priority in management as they are prone to poorer outcomes.

Hyunwook Ryu,1 Hyun Chul Kim,1 Inseung Jeon,1 In-Jin Jang,1 Joo-Youn Cho,1,2 Kyung Tae Kim,3 Jaeseong Oh1,4,5 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; 3Addpharma, Inc., Yongin-si, Gyeonggi-do, Republic of Korea; 4Department of Pharmacology, Jeju National University College of Medicine, Jeju, Republic of Korea; 5Clinical Research Institute, Jeju National University Hospital, Jeju, Republic of KoreaCorrespondence: Jaeseong Oh, Department of Pharmacology, Jeju National University College of Medicine, Jeju, Republic of Korea, Email jaeseong5@jejunu.ac.krBackground: Management of hypertension and hyperlipidemia, which are common comorbid risk factors for cardiovascular diseases, require multiple medications. The development of a fixed-dose combination (FDC) containing ezetimibe, rosuvastatin, telmisartan, and amlodipine aims to enhance patient adherence and persistence, but the potential interactions among the four medications have not been studied. This study aimed to evaluate the pharmacokinetic (PK) interactions between the FDC of ezetimibe/rosuvastatin 10/20 mg (ER) and the FDC of telmisartan/amlodipine 80/5 mg (TA).Methods: An open-label, single-sequence, three-period, three-treatment crossover study was conducted in healthy male subjects. All subjects received ER for 7 days, TA for 9 days and ER combined with TA for 7 days during each treatment period. For PK analysis of total/free ezetimibe, rosuvastatin, telmisartan, and amlodipine, serial blood samples were collected for 24 hours at steady state. Safety profiles were assessed throughout the study.Results: Thirty-eight subjects were enrolled, and 34 subjects completed the study. The systemic exposure to each active ingredient after coadministration of the two FDCs was similar to that after each FDC alone. The geometric mean ratios and 90% confidence intervals for the maximum plasma concentration (μg/L) and the area under the plasma concentration-time curve (h·μg/L) of the combination therapy to monotherapy, assessed at steady state, were as follows: total ezetimibe, 1.0264 (0.8765– 1.2017) and 0.9359 (0.7847– 1.1163); free ezetimibe, 1.5713 (1.2821– 1.9257) and 0.9941 (0.8384– 1.1788); rosuvastatin, 2.1673 (1.7807– 2.6379) and 1.1714 (0.9992– 1.3733); telmisartan, 1.0745 (0.8139– 1.4186) and 1.1057 (0.8379– 1.4591); and amlodipine, 0.9421 (0.8764– 1.0126) and 0.9603 (0.8862– 1.0405). Both combination therapy and monotherapy were well tolerated by the subjects.Conclusion: The coadministration of ezetimibe/rosuvastatin 10/20 mg and ezetimibe/rosuvastatin 10/20 mg was well tolerated in healthy subjects, and the PK interaction between those two FDCs was not clinically significant.Keywords: drug‒drug interactions, pharmacokinetics, fixed-dose combination, ezetimibe, rosuvastatin, telmisartan, amlodipine

Abstract Introduction Dexketoprofen/tramadol 25/75 mg (DKP/TRAM) is a fixed-dose combination of a cyclooxygenase inhibitor and opioid receptor agonist. To better understand the efficacy and safety of DKP/TRAM in the treatment of moderate to severe acute lower back pain (LBP) with or without radiculopathy, we carried out a large explorative phase IV international, multicenter, prospective, randomized, double-blind, parallel group, placebo-controlled study (DANTE). Methods A total of 538 patients with or without a history of LBP and experiencing acute LPB of moderate to severe intensity [Numerical Rating Scale-Pain Intensity (NRS-PI) score > 5] were randomized 4:4:1:1 to DKP/TRAM 25/75 mg every 8 h (n = 211), tramadol (TRAM) 100 mg (n = 207), placebo-matched DKP/TRAM (n = 59), or placebo-matched TRAM (n = 61). Results The proportion of patients achieving the primary endpoint, defined as the time to first achieve NRS-PI score

Aim: The present study compared the safety, efficacy, and tolerability of the new fixed-dose combination (FDC) of telmisartan 40 mg + bisoprolol 5 mg (TBP) tablets with the existing comparator FDC telmisartan 40 mg + metoprolol succinate ER 50 mg (TMS) tablets in patients with stage 1 and stage 2 hypertension. Methodology: The multicentric, double-blind, parallel-group, comparative, prospective, phase-III clinical study involved 264 subjects with stage 1 and stage 2 hypertension from 10 centres across India. The selected subjects were randomized into two groups: group A received the TMS and group B received the new FDC TBP. The primary endpoint was the mean change in seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) from baseline to week 12 in both the control and study arms. The secondary endpoint was achieving the target of SeSBP

Background: Uncontrolled blood pressure is a major risk factor for cardiovascular diseases. Fixed-dose combination (FDC) therapy offers a promising approach to addressing this challenge by providing a convenient single-tablet solution that enhances the effectiveness of blood pressure control. In our systematic review, we assess the effectiveness of perindopril/amlodipine FDC in managing blood pressure. Methods: We conducted a comprehensive search across four primary electronic databases, namely, PubMed, Virtual Health Library (VHL), Global Health Library (GHL), and Google Scholar, as of 8 February 2022. Additionally, we performed a manual search to find relevant articles. The quality of the selected articles was evaluated using the Study Quality Assessment Tools (SQAT) checklist from the National Institute of Health and the ROB2 tool from Cochrane. Results: Our systematic review included 17 eligible articles. The findings show that the use of perindopril/amlodipine FDC significantly lowers blood pressure and enhances the quality of blood pressure control. Compared to the comparison group, the perindopril/amlodipine combination tablet resulted in a higher rate of blood pressure response and normalization. Importantly, perindopril/amlodipine FDC contributes to improved patient adherence with minimal side effects. However, studies conducted to date have not provided assessments of the cost-effectiveness of perindopril/amlodipine FDC. Conclusion: In summary, our analysis confirms the effectiveness of perindopril/amlodipine FDC in lowering blood pressure, with combination therapy outperforming monotherapy and placebo. Although mild adverse reactions were observed in a small subset of participants, cost-effectiveness assessments for this treatment remain lacking in the literature. [ABSTRACT FROM AUTHOR]

The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed‐dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single‐center, randomized, open‐label, 3‐way crossover, single‐dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (Cmax) and area under the plasma analyte concentration–time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of Cmax and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated. [ABSTRACT FROM AUTHOR]

Rivaroxaban and aspirin are commonly used antithrombotic agents in combination to prevent coronary artery disease (CAD) and atherothrombotic events in adult patients after acute coronary syndrome (ACS) with elevated cardiac biomarkers, or with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD) in high-risk patients. The recommended dosage is 2.5 mg rivaroxaban twice daily in combination with 75–100 mg aspirin once daily. This study aimed to develop a fixed-dose combination tablet of rivaroxaban (2.5 mg) and aspirin (50 mg) to enhance medication adherence and decrease pill burden.Compatibility studies were conducted on the active ingredients to develop the product formula. The formula and the manufacturing procedure were chosen based on the risk assessment for each active substance, wet granulation with both actives intragranular was found to have faster dissolution than direct mix formulae. Furthermore, a validated reverse-phase HPLC stability indicator method was developed to detect APIs and their possible degradants.

Abstract The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed‐dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single‐center, randomized, open‐label, 3‐way crossover, single‐dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (Cmax) and area under the plasma analyte concentration–time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of Cmax and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated.

Background Hypertension and hypercholesterolemia are important risk factors for cardiovascular disease, and treatment with fixed‐dose combination (FDC) regimens is recommended by current guidelines. However, the clinical outcomes of different FDC dosages remain unknown. This study aimed to examine the clinical outcomes of FDC regimens and the free combination of amlodipine and atorvastatin at different dosages. Methods and Results Patients with concurrent hypertension and hypercholesterolemia treated daily with an FDC of 5 mg amlodipine and 10 mg atorvastatin (5/10 fixed group), and FDC of 5 mg amlodipine and 20 mg atorvastatin (5/20 fixed group), or free combination of 5 mg amlodipine and 20 mg atorvastatin (5/20 free group) were identified from the National Health Insurance Research Database of Taiwan. The primary outcome was the composite cardiovascular outcomes, including cardiovascular death, acute myocardial infarction, stroke, and coronary intervention. A total of 9095 patients were eligible for inclusion. The incidence of primary outcome per 1000 person‐years was 16.6 in the 5/10 fixed group, 12.6 in the 5/20 fixed group, and 16.5 in the 5/20 free group (5/20 fixed versus 5/20 free: hazard ratio [HR], 0.76 [95% CI, 0.64–0.91]; 5/20 fixed versus 5/10 fixed: HR, 0.76 [95% CI, 0.63–0.90]). Conclusions Among patients with concomitant hypertension and hypercholesterolemia, treatment with an FDC of amlodipine and high‐dose atorvastatin led to a lower risk of a composite of cardiovascular outcomes than treatment with the free combination or a similar FDC with a lower dose of atorvastatin.

The purpose of this study was to enhance the stability of montelukast and levocetirizine for the development of a fixed-dose combination (FDC) monolayer tablet. To evaluate the compatibility of montelukast and levocetirizine, a mixture of the two drugs was prepared, and changes in the appearance characteristics and impurity content were observed in a dry oven at 60 °C. Excipients that contributed minimally to impurity increases were selected to minimize drug interactions. Mannitol, microcrystalline cellulose, croscarmellose sodium, hypromellose, and sodium citrate were chosen as excipients, and montelukast–levocetirizine FDC monolayer tablets were prepared by wet granulating the two drugs separately. A separate granulation of montelukast and levocetirizine, along with the addition of sodium citrate as a pH stabilizer, minimized the changes in tablet appearance and impurity levels. The prepared tablets demonstrated release profiles equivalent to those of commercial products in comparative dissolution tests. Subsequent stability testing at 40 ± 2 °C and 75 ± 5% RH for 6 months confirmed that the drug content, dissolution rate, and impurity content met the specified acceptance criteria. In conclusion, the montelukast–levocetirizine FDC monolayer tablet developed in this study offers a potential alternative to commercial products.

Patients with type 2 diabetes (T2D) usually show progressive deterioration in glycemic control and sequential additions of therapy are generally needed. Many new options for glucose lowering therapy have been introduced recently and it is becoming common practice to use fixed-dose combinations (FDCs) of glucose lowering agents from different classes. This article reviews the FDC of canagliflozin with metformin extended release. A literature search was performed to identify publications describing the efficacy and safety of canagliflozin and metformin when used separately and in combinations. Canagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor which has shown benefits in reducing progression of renal disease and heart failure in patients with T2D. There was an increased incidence of amputation with canagliflozin in one study, but canagliflozin results in weight loss and reduction of blood pressure which contribute to the overall benefit. Metformin has been the first line oral hypoglycemic agent for many years and is thought to have many advantages, but it should be avoided in patients with severely decreased renal function because of the risk of lactic acidosis. The combination in a single tablet given once daily should help to simplify therapy and improve medication adherence in T2D. [ABSTRACT FROM AUTHOR]

The study aimed to develop a sensitive and high-throughput liquid chromatography coupled with tandem mass spectrometry method to quantify concentrations of tramadol and paracetamol simultaneously in human plasma. Sample preparation involved single-step protein precipitation using methanol and two deuterated internal standards, tramadol D6 and paracetamol D4. Agilent Poroshell 120 EC-C18 (100 × 2.1 mm, 2.1 µm) analytical column was employed to achieve chromatographic separation. Detection was in positive ion multiple reaction monitoring mode. A tailing factor (Tf) of <1.2, separation factor (K prime) of >1.5 from the column dead time and signal-to-noise (S/N) ratio >10, were obtained for analytes and internal standards. The standard curve was linear over the concentration range of 2.5–500.00 ng/mL for tramadol and 0.025–20.00 μg/mL for paracetamol. A small injection volume of 1 µL, low flow rate of 440 µL/min and short analysis time of 3.5 min reduced the solvent consumption, analysis cost and system contamination. The results of method validation parameters fulfilled the acceptance criteria of bioanalytical guidelines. The method was successfully applied to a bioequivalence study of fixed-dose combination products of tramadol and paracetamol in Malaysian healthy subjects. [ABSTRACT FROM AUTHOR]

Empagliflozin and metformin are oral antidiabetic drugs commonly used to treat type 2 diabetes mellitus as a combination therapy. This study aimed to compare the pharmacokinetics and safety of a newly developed fixed‐dose combination of 5‐mg empagliflozin L‐proline and 1000‐mg metformin with the reference drug. A randomized, open‐label, single‐dose, 2‐period, 2‐treatment, crossover study was conducted in healthy Korean subjects. The subjects received a single oral dose of reference drug or test drug at each period. The pharmacokinetic (PK) parameters were calculated using a noncompartmental method. The geometric mean ratios and 90% confidence intervals of the plasma maximum concentration (Cmax) and area under the concentration–time curve from time zero to the last quantifiable concentration (AUClast) were calculated. A total of 27 healthy subjects were included in the PK analysis. For empagliflozin, the geometric mean ratios (90% confidence intervals) of the test to reference drug for Cmax and AUClast were 1.03 (0.99–1.08) and 1.03 (1.00–1.06), respectively. For metformin, the corresponding values for Cmax and AUClast were 0.99 (0.92–1.06) and 1.00 (0.94–1.06), respectively. In conclusion, a fixed‐dose combination of empagliflozin L‐proline and metformin showed similar PK characteristics to the reference drug, and both drugs were safe in healthy subjects. [ABSTRACT FROM AUTHOR]

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Purpose of Review: The number of medications prescribed to patients has been progressively increasing, primarily driven by cardioprotective medications. The advent of pharmaceutical 3D printing technology holds the promise of reducing the burden of multiple pills by combining various medications with different release mechanisms into a single tablet. This development encourages a comprehensive review of the evidence supporting the use of combination pills. Recent Findings: Recent randomized studies have shown higher BP control rates in quadpill groups than in monotherapy groups and improved 6-month BP control rates with a low-dose triple fixed-dose combination (FDC) medication compared to usual care. Recent randomized controlled trials also support FDC use for primary and secondary prevention of cardiovascular disease. Three-dimensional printing technologies such as powder-based (PB) 3D printing, fused deposition modeling (FDM) 3D printing, and semisolid extrusion (EXT) 3D printing are examples of promising technologies that could be utilized to combine multiple medications with different release mechanisms into a single tablet. Summary: FDC therapy can provide patients with combination regimens with a reduced pill burden, which promotes improved adherence and efficacy. Recent randomized trials have shown that FDC can be used for primary and secondary prevention of cardiovascular disease with no significant difference in adverse events. Multidisciplinary approaches should be implemented to enhance long-term adherence, and further research on establishing affordable and effective initial dual antihypertensive therapy options is necessary. Pharmaceutical 3D printing technology may play an important role in enhancing the flexibility, affordability, and feasibility of clinical FDC utilization. [ABSTRACT FROM AUTHOR]

Histamine and cysteinyl leukotrienes (CysLTs) are potent inflammatory mediators in allergic rhinitis (AR). Studies involving other combinations of antihistaminics (Levocetirizine) and highly selective leukotriene receptor antagonist (LTA) (Montelukast) combination have shown additive benefits and are widely prescribed for AR. Evaluate the efficacy and safety of Bilastine 20 mg and Montelukast 10 mg fixed-dose combination (FDC) therapy in patients with AR. A randomized, double-blind, comparative, parallel, phase III study was conducted to evaluate efficacy and safety of Bilastine 20 mg and Montelukast 10 mg FDC at 16 tertiary care otolaryngology centres in India. Adult patients with AR for one year with IgE antibody positive and 12-h NSS score >36 in 3 days were randomized to receive either Bilastine 20 mg and Montelukast 10 mg or Montelukast 10 mg & Levocetirizine 5 mg tablets for 4 weeks. The change in total symptom score (nasal symptom scores (NSS) & non-nasal symptom scores (NNSS)) from baseline to week 4 was assessed as primary endpoint. Secondary endpoints included changes in TSS, NSS, NNSS, individual symptom scores (ISS), Rhinoconjunctivitis Quality of Life (RQLQ), discomfort due to rhinitis (VAS), and clinical global impression (CGI) scores. The change in mean TSS from baseline to week 4 in Test group (16.6 units) was comparable to reference group (17 units) (p= 0.8876). The difference in change in mean NSS, NNSS and ISS from baseline to day 7, 14, 28 were comparable. RQLQ improved from baseline to Day 28. Significant improvements were observed in discomfort due to AR measured by VAS and CGI scores from baseline to day 14 and 28. The safety and tolerability of patients were comparable between the groups. All adverse events (AEs) were mild to moderate in severity. No patient discontinued due to AEs. The FDC of Bilastine 20 mg and Montelukast 10 mg was efficacious and well tolerated in Indian patients with AR. [ABSTRACT FROM AUTHOR]

Background. We aimed to estimate the trends in dispensing rate and the spectrum of all state-funded lipid-lowering medications (LLMs) in Latvia over a decade. Methods. Using data from the National Health Service of the Republic of Latvia, we retrospectively analyzed all dispensed LLM-containing drug units in a ten-year period from 2012 to 2021. Results. In Latvia, 318.2 million oral and 994 subcutaneous units of LLMs were dispensed over a decade. Statins were the most dispensed LLMs (94.5%), and their use doubled from 19.7 to 43.5 million units. The proportion of high-intensity statins increased from 31.3% to 45.2%. The dispensing rate of ezetimibe increased from 184.7 thousand to 4.8 million. The share of fixed-dose statin combinations with ezetimibe grew from 0.2% to 10.0% among all statins and from 22.2% to 90.9% among all ezetimibe units. Statin use for primary and secondary prevention increased from 7.0 to 19.9 million and from 12.8 to 23.6 million units, respectively. Conclusion. The dispensing rate of statins doubled, and the use of ezetimibe increased more than 25 times in Latvia over a decade. The proportion of high-intensity statins increased from one third to almost half of all statins. Fixed-dose statin combinations with ezetimibe became frequently used. [ABSTRACT FROM AUTHOR]

Background: To assess the effectiveness and safety of a fixed-dose combination (FDC) of mebeverine hydrochloride 135 mg and chlordiazepoxide 5 mg in the management of irritable bowel syndrome (IBS) in Indian patients. Methods: This was an 8-week, prospective, open-label, observational study. Patients (n = 60, age: 18–60 years) newly diagnosed with IBS and having anxiety symptoms (score ≥18 on Hamilton Anxiety Rating Scale [HAM-A]), who were prescribed the study drug as a part of routine practice were included. Results: All 60 enrolled patients completed the study. Patients' mean standard deviation (SD) age was 37.45 (11.00) years; most were male (73.33%). The mean (SD) IBS-symptoms severity scale (IBS-SSS) score at baseline was 182.72 (84.39) indicating moderate symptom severity; the mean change at week 8 was 85.50 (82.69), P < 0.0001 (primary endpoint), and at week 4 was 64.70 (58.44), P < 0.0001. The mean (SD) IBS-36 score was 78.33 (41.87) at baseline and decreased at week 8 by 45.88 (34.92), P < 0.0001. At week 8, majority of patients achieved a ≥50-point improvement in IBS-SSS score (73.33%), and a ≥10-point improvement in IBS-36 scores (88.33%). The mean (SD) HAM-A total score was 26.97 (6.72) at baseline and decreased to 10.45 (8.99) at week 8, P < 0.0001. Three adverse drug reactions unlikely to be related to study drug were reported in two patients (nausea n = 1, headache n = 2). Good tolerability to study drug was reported by all patients and investigators at week 8. Conclusion: The FDC of mebeverine hydrochloride and chlordiazepoxide was effective in the treatment of IBS and was well tolerated. [ABSTRACT FROM AUTHOR]

A fixed combination of Nivolumab and Relatlimab (OPDUALAG) are human monoclonal antibodies (mAb) that are extensively used to treat skin cancer melanoma. The current investigation is to develop a robust, stability-indicating, and rapid method for the simultaneous determination of these two drugs by using the RP-UPLC technique. By utilizing this technique, the final chromatographic conditions were achieved with a Luna C18 column (50 x 2.1 mm, 1.6 μm), and a mobile phase made with acetonitrile and 0.1% formic acid, 6:4 ratio, respectively (Diluted 1.0 mL of Formic acid in 1000 mL of HPLC grade water) by adapting isocratic elution. Both Nivolumab and Relatlimab were detected at 229 nm, and a satisfactory separation was achieved in 3.0 minutes of run time with a flow rate of 0.2 mL/min. The method is linear from 15 - 90 μg/mL for Nivolumab (R2 = 0.9996) and 5 - 30 μg/mL for Relatlimab (R2 = 0.9997). Results of method repeatability for Nivolumab (% RSD=1.3 %) and Relatlimab (% RSD=0.48 %) and intermediate precision Nivolumab (% RSD=1.1 %) and Relatlimab (% RSD=0.48%) were found within acceptable limits. Also, the forced degradation study results show that it is discernible; the degradation products of both drugs were separated from the main peak, which demonstrates the efficiency of the stability-indicating method. So this method works well for routine analysis and stability studies. [ABSTRACT FROM AUTHOR]

Community-acquired infections (CAIs) represent a major burden for health-care system. This directly aids the emergence of antibiotic-resistant organisms. India is not immune to it. This review assessed the current guideline recommendations for the usage of oral cephalosporins in the management of common CAIs. The researchers conducted iterative searches in PubMed, SCOPUS, and Google Scholar for published articles using various keywords. The search was conducted in November 2022 and considered articles published till date. Different CAIs are caused by similar organisms, susceptible to first-line antibiotics such as penicillin and cephalosporins. Most of the guidelines recommend the use of oral cephalosporins for the management of the commonly prevalent CAIs. These antibiotics however should be used as a monotherapy and not as fixed-dose combinations (FDCs), as FDCs with oral cephalosporins lack scientific basis and may be detrimental. For burden of CAIs intensified by anti-microbial resistance, guidelines are useful for the management of CAIs to educate the prescribers and preserve currently available antibiotics.

Abstract Introduction The objective of the present study was to evaluate the efficacy and safety of MP-AzeFlu nasal spray in comparison to commercially available azelastine hydrochloride and fluticasone propionate sprays in Chinese patients with moderate-to-severe allergic rhinitis (AR). Methods We conducted a 14-day multicenter, randomized, double-blind, active controlled prospective clinical study in adult and adolescent patients with AR, who had moderate-to-severe symptoms. The primary efficacy endpoint was the change from baseline in combined 12-h reflective total nasal symptom score (rTNSS) (morning [AM] + afternoon [PM]). The safety profile of the study medications was assessed through the recording, reporting, and analysis of baseline medical conditions, adverse events (AEs), vital signs, and focused nasal examination. Three hundred patients per treatment group were randomized, which led to a total sample size estimation of 900 patients. Results MP-AzeFlu group showed significantly higher symptom reduction for the entire 2-week treatment period in rTNSS when compared with the AZE group (LS mean difference: − 1.96; 95% CI: − 2.53, − 1.39; p

Abstract Although the cardiovascular (CV) polypill concept is not new and several guidelines state that a CV polypill should be considered an integral part of a comprehensive CV disease (CVD) prevention strategy, there are still some barriers to its implementation in the real-world setting, mainly in secondary CV prevention. As the CNIC-polypill is the only one approved for secondary CV prevention in patients with atherosclerotic CVD in 27 countries worldwide, a panel of four discussants and 30 participants from 18 countries conveyed in a virtual meeting on April 21, 2022, to discuss key clinical questions regarding the practical use of the CNIC-Polypill and barriers to its implementation. Data presented showed that, although the use of the CV polypill is not explicitly mentioned in the current 2021 European Society of Cardiology guidelines on CVD prevention, it may be used in any patient for secondary CVD prevention tolerating all their components to improve outcomes through different aspects. The favourable results of the Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) trial now reinforce this recommendation. The panellists presented algorithms on how to switch from any baseline regimen when starting treatment with the CNIC-polypill in different situations, including patients with hypertension, dyslipidaemia, and a previous CV event; at discharge after a cardiovascular event; in chronic ischemic conditions; and in cases of polypharmacy. The panellists and expert discussants did agree that available studies conducted so far with the CNIC-polypill demonstrate that it is as efficacious as the monocomponents, equipotent drugs, or other therapies; reduces the risk of experiencing recurrent major CV events; improves medication adherence; reduces health care costs and resources compared to patients treated with loose drugs; and the patients prefer it over the multipill strategy. In conclusion, the data presented by the participants provided the evidence behind the use of the CNIC-polypill to help fulfil the goal of encouraging its adoption by physicians.

The aim of the work is to assess the effectiveness of prescribing a fixed-dose combination of amlodipine with the ACE inhibitor lisinopril or with the angiotensin 2 receptor blocker valsartan in patients with coronary artery disease, acute coronary syndrome with hypertensive disease regarding the impact on the structural and functional parameters of the heart and extracranial branches of the brachiocephalic arteries. Materials and methods. General clinical examination of 108 patients with postinfarction cardiosclerosis and hypertension was done within 12 months. The patients were allocated to two groups. Patients in the first group (n = 50) were assigned a fixed-dose combination of lisinopril and amlodipine (20 mg and 5 mg, respectively), and patients in the second group (n = 58) received a fixed-dose combination of valsartan with amlodipine (160 mg and 5 mg, respectively). The patients were monitored for 12 months, including general clinical examinations, measurements of office blood pressure (BP), 24-hour BP monitoring, echo-dopplerographic examination of the heart and brachiocephalic arteries, determination of the composite endpoint. Statistical analysis of the obtained data was performed using Microsoft Excel, IBM SPSS Statistics v.23. Results. A significant difference in echocardiographic data has been proved (p < 0.05) regarding left ventricle (LV) dimensions in both study groups. A significant decrease in the E/A ratio and an insignificant decrease in E/E’ (p > 0.05) have been found in the first group. When analyzing the indicators of diastolic function in the second group, a highly significant (p < 0.05) decrease in E/A, E/E’, IO of the LA has been revealed; data analysis on the morphofunctional state indicators of the extracranial arteries has shown a CIM reduction and a decrease in PSV and RI. Conclusions. Prescriptions of the fixed-dose combination of amlodipine with the ACE inhibitor lisinopril was more effective in terms of the LV measurements (p < 0.05) and LV diastolic function as evidenced by decreased E/A, E/E’ and IO of the LA (p < 0.05) as compared to the data in the group of amlodipine with the angiotensin 2 receptor blocker valsartan. Both fixed-dose combinations were effective in reducing the CIM thickness, decreasing PSV and RI when analyzing the morphofunctional state findings of the extracranial arteries.

AbstractThe study aimed to develop a sensitive and high-throughput liquid chromatography coupled with tandem mass spectrometry method to quantify concentrations of tramadol and paracetamol simultaneously in human plasma. Sample preparation involved single-step protein precipitation using methanol and two deuterated internal standards, tramadol D6 and paracetamol D4. Agilent Poroshell 120 EC-C18 (100 × 2.1 mm, 2.1 µm) analytical column was employed to achieve chromatographic separation. Detection was in positive ion multiple reaction monitoring mode. A tailing factor (Tf) of 1.5 from the column dead time and signal-to-noise (S/N) ratio >10, were obtained for analytes and internal standards. The standard curve was linear over the concentration range of 2.5–500.00 ng/mL for tramadol and 0.025–20.00 μg/mL for paracetamol. A small injection volume of 1 µL, low flow rate of 440 µL/min and short analysis time of 3.5 min reduced the solvent consumption, analysis cost and system contamination. The results of method validation parameters fulfilled the acceptance criteria of bioanalytical guidelines. The method was successfully applied to a bioequivalence study of fixed-dose combination products of tramadol and paracetamol in Malaysian healthy subjects.

Introduction: The objective of the present study was to evaluate the efficacy and safety of MP-AzeFlu nasal spray in comparison to commercially available azelastine hydrochloride and fluticasone propionate sprays in Chinese patients with moderate-to-severe allergic rhinitis (AR). Methods: We conducted a 14-day multicenter, randomized, double-blind, active controlled prospective clinical study in adult and adolescent patients with AR, who had moderate-to-severe symptoms. The primary efficacy endpoint was the change from baseline in combined 12-h reflective total nasal symptom score (rTNSS) (morning [AM] + afternoon [PM]). The safety profile of the study medications was assessed through the recording, reporting, and analysis of baseline medical conditions, adverse events (AEs), vital signs, and focused nasal examination. Three hundred patients per treatment group were randomized, which led to a total sample size estimation of 900 patients. Results: MP-AzeFlu group showed significantly higher symptom reduction for the entire 2-week treatment period in rTNSS when compared with the AZE group (LS mean difference: − 1.96; 95% CI: − 2.53, − 1.39; p < 0.0001), or the FLU group (LS mean difference: − 0.98; 95% CI: − 1.55, − 0.41; p = 0.0007). The results of adult RQLQ showed improvement in QoL in all treatment groups. Except for dysgeusia (bitter taste) that was reported by more patients (13 [4.3%]) in the MP-AzeFlu group, the incidence of all other TEAEs in the MP-AzeFlu group was comparable or even lower than in other treatment groups. Conclusions: MP-AzeFlu, when administered as one spray per nostril twice daily for 14 days, alleviated AR symptoms in Chinese patients with moderate-to-severe AR. Trial Registration: Clinicaltrials.gov; NCT03599791, Registered June 29, 2018, retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03599791. [ABSTRACT FROM AUTHOR]

Community-acquired infections (CAIs) represent a major burden for health-care system. This directly aids the emergence of antibiotic-resistant organisms. India is not immune to it. This review assessed the current guideline recommendations for the usage of oral cephalosporins in the management of common CAIs. The researchers conducted iterative searches in PubMed, SCOPUS, and Google Scholar for published articles using various keywords. The search was conducted in November 2022 and considered articles published till date. Different CAIs are caused by similar organisms, susceptible to first-line antibiotics such as penicillin and cephalosporins. Most of the guidelines recommend the use of oral cephalosporins for the management of the commonly prevalent CAIs. These antibiotics however should be used as a monotherapy and not as fixed-dose combinations (FDCs), as FDCs with oral cephalosporins lack scientific basis and may be detrimental. For burden of CAIs intensified by anti-microbial resistance, guidelines are useful for the management of CAIs to educate the prescribers and preserve currently available antibiotics. [ABSTRACT FROM AUTHOR]

Although the cardiovascular (CV) polypill concept is not new and several guidelines state that a CV polypill should be considered an integral part of a comprehensive CV disease (CVD) prevention strategy, there are still some barriers to its implementation in the real-world setting, mainly in secondary CV prevention. As the CNIC-polypill is the only one approved for secondary CV prevention in patients with atherosclerotic CVD in 27 countries worldwide, a panel of four discussants and 30 participants from 18 countries conveyed in a virtual meeting on April 21, 2022, to discuss key clinical questions regarding the practical use of the CNIC-Polypill and barriers to its implementation. Data presented showed that, although the use of the CV polypill is not explicitly mentioned in the current 2021 European Society of Cardiology guidelines on CVD prevention, it may be used in any patient for secondary CVD prevention tolerating all their components to improve outcomes through different aspects. The favourable results of the Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) trial now reinforce this recommendation. The panellists presented algorithms on how to switch from any baseline regimen when starting treatment with the CNIC-polypill in different situations, including patients with hypertension, dyslipidaemia, and a previous CV event; at discharge after a cardiovascular event; in chronic ischemic conditions; and in cases of polypharmacy. The panellists and expert discussants did agree that available studies conducted so far with the CNIC-polypill demonstrate that it is as efficacious as the monocomponents, equipotent drugs, or other therapies; reduces the risk of experiencing recurrent major CV events; improves medication adherence; reduces health care costs and resources compared to patients treated with loose drugs; and the patients prefer it over the multipill strategy. In conclusion, the data presented by the participants provided the evidence behind the use of the CNIC-polypill to help fulfil the goal of encouraging its adoption by physicians. [ABSTRACT FROM AUTHOR]

Background and Aims: Epilepsy is one of the most disabling and most common neurological disorders, affecting approximately 65 million people of all age groups worldwide. When there is no response to monotherapy in the treatment of epilepsy, the combined use of Carbamazepine (CARBA) and Levetiracetam (LEV), which have different mechanisms of action, can be additive/synergistic and may be useful in the clinic. The aim of our study is to develop a fixed-dose combination (FDC)- nanoemulsion (NE) formulation containing CARBA and LEV for the treatment of epilepsy. Methods: Blank NE (BLNK-NE) and CARBA+LEV-FDC-NE formulations were prepared and carried out the in vitro characterization studies [morphological analysis, centrifugation test, droplet size (DS), polydispersity index (PDI), zeta potential (ZP), viscosity and pH measurements, FT-IR analysis, the percent entrapment efficiency (EE%), and in vitro release study]. Results: The DS, PDI, pH, and ZP values for the BLNK-NE formulation were found to be 117.63±3.82 nm, 0.240±0.014, 4.62±0.03, and (-)26.07±3.04 mV, respectively. For the CARBA+LEV-FDC-NE formulation, the DS, PDI, pH, and ZP values were determined as 137.56±3.11 nm, 0.225±0.013, 4.60±0.06, and (-)21.62±0.29 mV, respectively. The EE% values obtained for CARBA+LEV-FDC-NE were 97.33±0.56% (for CARBA) and 96.73±0.91% (for LEV). Conclusion: The CARBA+LEV-FDC-NE formulation was successfully prepared. This formulation had suitable in vitro characterization results. [ABSTRACT FROM AUTHOR]

The combination of non-steroidal anti-inflammatory drugs (NSAIDs) with non-opioid analgesics is common in clinical practice for the treatment of acute painful conditions like post-operative and post-traumatic pain. Despite the satisfactory results achieved by oral analgesics, parenteral analgesia remains a key tool in the treatment of painful conditions when the enteral routes of administration are inconvenient. Parenteral ready-to-use fixed-dose combinations of non-opioid analgesics combinations, including NSAIDs and paracetamol or metamizole, could play a central role in the treatment of painful conditions by combining the advantages of multimodal and parenteral analgesia in a single formulation. Surprisingly, only in 2020, a parenteral ready-to-use fixed-dose combination of ibuprofen/paracetamol was launched to the market. This review aims to investigate the current availability of combinations of NSAIDs with paracetamol or metamizole in both European and American markets, and how the combination of such drugs could play a central role in a multimodal analgesia strategy. Also, we explored how the parenteral formulations of NSAIDs, paracetamol, and metamizole could serve as starting elements for the development of new parenteral ready-to-use fixed-dose combinations. We concluded that, despite the well-recognized utility of combining NSAIDs with paracetamol or metamizole, several randomized clinical trial studies demonstrate no clear advantages concerning their efficacy and safety. Future clinical trials specifically designed to assess the efficacy and safety of pre-formulated fixed-dose combinations are required to generate solid evidence about their clinical advantages. [ABSTRACT FROM AUTHOR]

[Display omitted] In situ gelling systems (ISGS) can prolong retention time and bioavailability of ophthalmic solutions. The complexity and cost of ISGS avert their industrial scale-up and clinical implementation. In this study, we demonstrate novel application of hot-melt extrusion (HME) technology for continuous manufacturing of ISGS (MeltDrops Technology). Timolol maleate (TIM) and dorzolamide hydrochloride (DRZ) loaded MeltDrops were successfully developed using HME for glaucoma management, thereby resolving issues with batch manufacturing of ISGS, prolonging retention time thus improving bioavailability. The MeltDrops technology involves one-step, i.e., passing all the ingredients through an extruder at a screw speed between 20 and 50 rpm and barrel temperature of 80 °C. The comparative evaluation of MeltDrops and batch-processed ISGS demonstrated that MeltDrops exhibited better physical and chemical content uniformity. The extrusion temperature and screw speed were critical factors influencing content uniformity and properties of the MeltDrops. MeltDrops showed sustained drug release for > 12 h in vitro (TIM = 83.07%; DRZ = 60.43%, 12 h) versus marketed eyedrops. The developed MeltDrops followed Peppas-Sahlin model, combining Fickian diffusion and swelling processes. The in vivo study in New Zealand rabbits revealed superior effectiveness and safety of the MeltDrops as compared to the marketed eyedrops. Herein we conclude, MeltDrops would serve as a cutting-edge platform technology that can be used to manufacture various ISGS with one-step processability, cost-effectiveness, and improved product quality, which are otherwise processed by batch manufacturing that involves numerous complex processing steps. [ABSTRACT FROM AUTHOR]

Introduction: This study compared efficacy and safety of triple drug fixed-dose combination (FDC) of dapagliflozin (DAPA) + sitagliptin (SITA) + metformin (MET) extended release (ER) with SITA + MET sustained release (SR) and DAPA + MET ER in patients with type 2 diabetes poorly controlled with metformin. Methods: This phase 3, randomized, open-label, active-controlled study included adult patients with glycated hemoglobin (HbA1c) ≥ 8% (64 mmol/mol) and ≤ 11% (97 mmol/mol), randomized in 1:1:1 ratio to receive either FDC of DAPA + SITA + MET ER (10 mg + 100 mg + 1000 mg) tablets once daily (n = 137) or co-administration of SITA + MET SR (100 mg + 1000 mg) tablets once daily (n = 139) or FDC of DAPA + MET ER (10 mg + 1000 mg) tablets once daily (n = 139). Primary endpoint was mean change in HbA1c from baseline to week 16. Results: Mean baseline HbA1c was approximately 9% (75 mmol/mol) in each treatment group. At week 16, adjusted mean reduction in HbA1c from baseline was significantly greater with DAPA + SITA + MET ER (− 1.73% [− 19.0 mmol/mol]) compared to SITA + MET SR (− 1.28% [− 14.1 mmol/mol]; difference of − 0.46% [− 5.1 mmol/mol], p < 0.001) and DAPA + MET ER (− 1.33% [− 14.6 mmol/mol]; difference − 0.4% [4.4 mmol/mol], p < 0.001). Similarly, at week 12, reduction in HbA1c from baseline was significantly greater with DAPA + SITA + MET ER compared to SITA + MET SR (p = 0.0006) and DAPA + MET ER (p = 0.0276). At week 16, DAPA + SITA + MET ER showed significant reduction in postprandial blood glucose compared to DAPA + MET ER (p = 0.0394) and significant reduction in fasting blood glucose with DAPA + SITA + MET ER compared to SITA + MET SR (p = 0.0226). The proportion of patients achieving HbA1c < 7.0% (53 mmol/mol) at week 16 was significantly higher with DAPA + SITA + MET ER (38.5%) versus SITA + MET SR (12.8%) (p < 0.001) and DAPA + MET ER (21.3%) (p = 0.0023). All study medications were well tolerated. Conclusion: Triple FDC of DAPA + SITA + MET ER tablets once daily was significantly better in achieving glycemic control versus dual combination once daily in patients with type 2 diabetes poorly controlled with metformin without any significant safety concerns. Trial Registration: CTRI/2021/11/038176, registered on 22 November 2021. Plain Language Summary: Type 2 diabetes is a progressive disease in which the risks of microvascular and macrovascular complications and mortality are strongly associated with hyperglycemia. Achieving glycemic control remains the main goal of treatment to prevent these complications. Estimates in 2019 showed that 77 million individuals had diabetes in India, which is expected to rise over 134 million by 2045. Considering the progressive nature of the disease, many guidelines recommend use of dual or triple drug therapy based on glycated hemoglobin (HbA1c) level. Use of fixed-dose combination (FDC) helps to improve therapy compliance and can provide optimum therapeutic benefits. Mechanisms of action of dipeptidyl peptidase 4 (DPP4) and sodium–glucose cotransporter 2 (SGLT2) inhibitors are complementary to that of metformin with low risk of hypoglycemia. Studies have shown beneficial effects of adding both DPP4 inhibitors and SGLT2 inhibitors after metformin monotherapy. This phase 3 study was designed to assess efficacy and safety of triple FDC of dapagliflozin + sitagliptin + metformin extended release in comparison with combipack of sitagliptin + metformin sustained release and FDC of dapagliflozin + metformin ER in patients with type 2 diabetes inadequately controlled with metformin monotherapy. The study demonstrated superiority of triple FDC of dapagliflozin + sitagliptin + metformin ER over dual combinations in terms of reduction in HbA1c and percentage of patients achieving target HbA1c at the end of week 16. The current study provides evidence for considering triple FDC of dapagliflozin + sitagliptin + metformin ER as an alternative option with minimal risk of hypoglycemia and weight gain, while considering oral triple-combination therapy for patients to achieve their glycemic target. [ABSTRACT FROM AUTHOR]

(1) Background: There is a high burden of poor glycemic control in the Indian population with type 2 diabetes mellitus (T2DM). Currently, the use of metformin sustained-release (SR)–vildagliptin fixed-dose combination (FDC) is very low as compared to metformin immediate-release (IR)–vildagliptin FDC which is associated with higher adverse events (AEs). Here, we present real-world effectiveness of metformin SR–vildagliptin FDC treatment in patients with T2DM; (2) Methods: This retrospective analysis was carried out from the medical records of adult T2DM patients visiting a single study center in India (December 2020–February 2021). A total of 10 patients (aged ≥20 years) were treated with vildagliptin 50 mg and metformin SR 500 mg FDC for 15 days. The treatment response was assessed by the percentage of time spent in the target glucose range (TIR at baseline and 15 days after treatment); (3) Results: The glycated hemoglobin (HbA1c) levels at baseline varied between 6.5% to 12%. The glycemic control improved in 70% of patients (mean increase in TIR: 18.9%). Treatment adherence was 100%. No gastrointestinal symptoms or AEs were reported; (4) Conclusions: Early intervention with metformin SR–vildagliptin FDC in patients with T2DM can ensure therapy compliance in terms of superior efficacy along with safety and tolerability. Key summary points: Early initiation of combination therapy helps in early achievement of glycemic goals; Early initiation of metformin and vildagliptin FDC results in significant glycemic control with good tolerability and compliance; Metformin SR–vildagliptin FDC has lower adverse events, compared to metformin IR–vildagliptin FDC; A case series of ten patients with T2DM treated with metformin SR–vildagliptin FDC is presented to assess the real-world effectiveness of this combination.

Abstract Fixed‐dose combination (FDC) therapy is recommended for hypertension management in Nigeria based on randomized trials at the individual level. This cluster‐randomized trial evaluates effectiveness and safety of a treatment protocol that used two‐drug FDC therapy as the second and third steps for hypertension control compared with a protocol that used free pill combinations. From January 2021 to June 2021, 60 primary healthcare centers in the Federal Capital Territory of Nigeria were randomized to a protocol using FDC therapy as second and third steps compared with a protocol that used the same medications in free pill combination therapy for these steps. Eligible patients were adults (≥18 years) with hypertension. The primary outcome was the odds of a patient being controlled at their last visit between baseline to 6‐month follow‐up in the FDC group compared to the free pill group. 4427 patients (mean [SD] age: 49.0 [12.4] years, 70.5% female) were registered with mean (SD) baseline systolic/diastolic blood pressure 155 (20.6)/96 (13.1) mm Hg. Baseline characteristics of groups were similar. After 6‐months, hypertension control rate improved in the two treatment protocols, but there were no differences between the groups after adjustment (FDC = 53.9% versus free pill combination = 47.9%, cluster‐adjusted p = .29). Adverse events were similarly low (

Objective: The objective of this study was to assess current practices and usage patterns of antihypertensive medications in managing hypertension (HTN) in India. Materials and Methods: A cross-sectional, observational digital study was conducted among health-care practitioners (HCPs) across India (November 2022–March 2023). Results: A total of 792 HCPs (cardiologists, consulting, and general physicians) participated in this study. According to 63.38% of HCPs, 20–50 essential HTN patients seek consultation weekly. The majority of patients were in the age range of 40–60 years (84.09%). A total of 67.55% of HCPs mentioned that systolic blood pressure (BP) ranged between 140 and 160 mmHg. Type 2 diabetes mellitus was the most common comorbidity among hypertensive patients (84.09%). In total, 53.79% and 37.37% of HCPs preferred angiotensin receptor blockers (ARBs)/angiotensin-converting enzyme and calcium channel blockers (CCBs) as the first choice of antihypertensive agents. The majority of HCPs (>69%) preferred prescribing a triple-drug fixed-dose combination (FDC) of CCBs + ARB + diuretics in hypertensive patients with coronary artery disease (CAD) and resistant HTN. The majority (89.90%) of HCPs preferred prescribing FDC of CCBs over monotherapy. Amlodipine (>55%) followed by cilnidipine (>32%) were preferred CCBs for young and older hypertensive patients. In patients with essential HTN without any CVD, amlodipine (72.85%) was the preferred CCB. Vascular selectivity (59.09%) and longer half-life (54.55%) were important factors for prescribing CCBs. Resistant HTN, inadequate BP control with monotherapy, and the presence of CAD were all (62.63%) important considerations for FDC with CCBs. The underutilization of CCBs in managing HTN (63.88%) was highlighted. Conclusion: Overall responses provide a comprehensive overview of the prevailing perception and the usage patterns of antihypertensive agents employed by HCPs in India.